Methods (brief)

In this first iteration of the living systematic review we searched for randomised controlled trials that compared pro-dopaminergic interventions to placebo in adults with unipolar depression (i.e. any standardised measure, above-threshold symptoms on any standardised measure, or a clinical diagnosis based on any operationalised criteria).

Eight databases were searched from inception up to the 9th of November, 2023 (see protocol for full search strings). Database search results were imported into EPPI-Reviewer and de-duplicated prior to screening. All steps related to record screening and data extraction were completed in EPPI-Reviewer.

Titles and abstracts of the identified records were screened by at least two reviewers (CF, MC, JK, JP). We retrieved the full-texts and any supporting documents for all records that were not excluded at the title and abstract screening stage. The full-text screening was conducted by at least two reviewers (CF, JK, JP, AK, EB). Conflicts at title and abstract, and full-text screening, were resolved through discussion between the two reviewers and involvement of a third reviewer (AC, EGO). Additional information on the full study eligibility criteria can be found in the pre-published protocol.

Relevant data was extracted using EPPI-Reviewer by at least two reviewers (CF, CA, EB, JK).

As specified in our protocol, we focused on:

For anhedonia and anxiety symptom severity, we extracted outcome data reported at 8 weeks post-treatment or manipulation. If the information at 8 weeks was not available, we considered eligible data ranging between 4 and 12 weeks (with preference to the time point closest to 8 weeks and, if equidistant, the longer outcome). For acceptability, tolerability, safety and safety (specific adverse events), we extracted outcome data reported at the end of the studies.

When extracting continuous outcomes we extracted mean and standard deviation to two decimal places. Where standard error was reported instead, we converted the value to standard deviation. Baseline and endpoint values were extracted, where only change in score and baseline or endpoint was reported, the missing value was calculated by adding or subtracting the change score to the baseline or endpoint.

When extracting dichotomous outcomes we extracted natural numbers and where only percentages of participant groups were reported, a value was calculated and rounded up to the nearest natural number. Adverse events were extracted using the exact terms they were reported in the included studies.

We assessed risk of bias with the RoB2 tool (Higgins et al. 2019). All outcomes for all included studies were assessed by at least two reviewers (JK, CF, CA, AH) and conflicts were resolved by discussion between reviewers (Flemyng et al, 2023). To evaluate biases due to missing evidence and biases across studies, the ROB-ME tool (Page et al, 2023) was used with the same double screening and conflict resolution process as described above.

Effect sizes were calculated as standardised mean differences (SMDs) for continuous outcomes (anhedonia and anxiety symptom severity) and odds ratios (ORs) for dichotomous outcomes (acceptability, tolerability, and specific-adverse events). We calculated the 95% confidence interval (CI) around the pooled effect size for each meta-analysis.

Meta-analyses were conducted using a random effects model with the inverse variance method, using the restricted maximum-likelihood estimator for tau2 and the Q-Profile method for the confidence interval of tau2. Confidence intervals were adjusted using the Hartung-Knapp method. Prediction intervals were calculated to better report the effect of heterogeneity on the overall pooled effect.

We conducted a series of sensitivity analyses on the primary outcome. We aggregated individual participant data (IPD) of randomised controlled trials on antidepressants in people with depression, performing a series of random effects network meta-analyses to compare the effects of pro-dopaminergic and non-pro-dopaminergic pharmacological interventions on anhedonia.

Subgroup analyses and meta-regressions were also conducted for the following variables: mean age of participants, mean anhedonia baseline score, mean anxiety baseline score, sex (proportion of female participants), and planned treatment duration. This was done using a mixed-effects model with the estimation of the between-study heterogeneity tau2 based on the REML method. Meta-regressions were only conducted for outcomes where data was available from 10 or more studies.

Summary of evidence tables were constructed for all outcomes including a summary of the meta-analytic result, biases within-study, across-study, and due to indirectness.

Please refer to the protocol and the extended data for more details.

A list of abbreviations can be found towards the end of the document.

Results

Below are the results of the systematic review and meta-analysis including a PRISMA flow diagram (Page et al 2021) for details of the flow of study selection, a table of characteristics for included studies, risk of bias assessment, forest plots for each outcome with accompanying descriptive text.

Description of included studies

We identified 61 eligible studies. The study characteristics for studies that reported anhedonia scores can be found in Table 1 and characteristics of studies that did not report anhedonia can be found in Table 2. Data from studies contributed with at least one outcome with quantitative data (total of 9975 participants), which included adults from multiple countries. The mean age of participants was 42.4 years (range 15 to 72 years), with a mean proportion of 0.58 female participants (range 0 to 0.86). Included studies allocated the participants to treatment lasting between 4 to 12.9 weeks (median, 6 weeks).

Author (Year) Country Sponsor Arms (in LSR) Setting Condition Treatment duration Intervention group Participants (n) Females (n) Age (mean) Age (SD) or range (specified) Dosage fixed or flexible Intervention format Planned dosage range (min-max mg/day) Delivered dosage range (min-max mg/day) Delivered dosage (mean mg/day) Anhedonia measure Baseline n Baseline anhedonia (mean (SD)) Follow-up n Follow-up anhedonia (mean (SD))
Bymaster (2011) Romania, Serbia, USA DOV Pharmaceuticals, Euthymics Bioscience 2 Secondary/Tertiary Care Depressive disorder 6 weeks Placebo 29 19 49.5 6.9 Fixed Oral
MADRS Anhedonia Factor 28 13.7 (1.6) 26 9.3 (1.58)
. . . . . . . Amitifadine 34 25 48.2 9.4 Fixed Oral 50mg to 50mg 25mg to 50mg
MADRS Anhedonia Factor 33 12.8 (2.1) 33 7.9 (74)
Hewett (2009) Austria, Belgium, Bulgaria, Croatia, Estonia, Finland, Greece, Ireland, Latvia, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden and Mexico GSK 2 NA Major depressive disorder 8 weeks Placebo 199 142 41.8 11.56 Flexible Oral
MEI Total 197 26.4 (12.79) 197 17.4 (19.37)
. . . . . . . Bupropion XR 188 138 41.8 11.68 Flexible Oral 150mg to 300mg NA 170.1mg MEI Total 187 26.8 (12.95) 187 24.6 (19.69)
Hewett (2010a) Australia, France, Germany, the Netherlands, Norway, South Africa and Sweden GSK 2 NA Major depressive disorder 8 weeks Placebo 189 125 44.5 10.79 Flexible Oral
MEI Total 186 25.3 (12.81) 186 18.3 (21.95)
NA NA NA NA NA NA NA Bupropion XR 204 127 45.6 11.76 Flexible Oral 150mg to 300mg 150mg to 300mg 180mg MEI Total 202 27.2 (13.5) 202 20.8 (21.74)
Hewett (2010b) Australia, Belgium, Canada, Croatia, Finland, France, Germany, India, Latvia, Netherlands, Norway, Poland, Republic of South Africa, Russia and United States GSK 2 NA Major depressive disorder 10 weeks Placebo 207 144 71.3 5.9 Flexible Oral
MEI Total 204 29.5 (15.16) 204 16.9 (23.42)
. . . . . . . Bupropion XR 211 157 70.9 5.6 Flexible Oral 150mg to 300mg 150mg to 300mg
MEI Total 210 29 (13.85) 210 23.6 (22.89)
Jefferson (2006) NA GSK 2 NA Major depressive disorder 8 weeks Placebo 139 96 39.8 16-69 (range) Flexible Oral
IDS-IVR-30 Pleasure scale
137 Change from baseline = -3.7 (4.61)
. . . . . . . NA NA NA NA NA NA NA NA NA NA IDS-C-30 Pleasure scale
133 Change from baseline = -5.3 (4.61)
. . . . . . . Bupropion XR 135 89 40.0 20-68 (range) Flexible Oral 150mg to 450mg 150mg to 450mg
IDS-IVR-30 Pleasure scale
133 Change from baseline = -6.7 (4.61)
. . . . . . . NA NA NA NA NA NA NA NA NA NA IDS-C-30 Pleasure scale
133 Change from baseline = -5.5 (4.61)
Koshino (2013) Japan, South Korea GSK 3 NA Major depressive disorder 10 weeks Placebo 186 85 37.9 11.09 Fixed Oral
MADRS item 8 186 3.7 (1.06) 186 2 (1.45)
. . . . . . . Bupropion 150mg 190 92 36.0 10.42 Fixed Oral 150mg 150mg
MADRS item 8 190 3.7 (1.16) 190 2 (1.45)
. . . . . . . Bupropion 300mg 188 83 37.5 10.96 Fixed Oral 300mg 300mg
MADRS item 8 188 3.7 (1.09) 188 2.1 (1.55)

Table 1. characteristics of included studies that reported anhedonia scores. NI=no information available

Author (Year) Country Sponsor Arms (in LSR) Setting Condition Treatment duration Intervention group Participants (n) Females (n) Age (mean) Age (SD) or range (specified) Dosage fixed or flexible Intervention format Planned dosage range (min-max mg/day) Delivered dosage range (min-max mg/day) Delivered dosage (mean mg/day)
A multicentre comparative… (1994) UK NI 2 NI Major depressive episode 6 weeks Placebo 54 NI NI NI Fixed Oral NI NI NI
. . . . . . . Moclobemide 56 NI NI NI Fixed Oral 450mg 450mg NI
Agosti (1991) USA NI 3 Secondary/Tertiary Care Non melancholic chro*c depression 6 weeks Phenelzine 10 NI NI NI Flexible Oral 60mg to 90mg NI NI
. . . . . . NI Placebo 23 NI NI NI Flexible Oral NI NI NI
. . . . . . . Selegiline (L-deprenyl) 12 NI NI NI Fixed Oral 40mg 40mg NI
Amsterdam (1989) USA Sanofi Research (partial grant) 5 NI Major depression 4 weeks Minaprine 100mg 34 12 41 12 Flexible Oral 100mg to 400mg NI 93mg
. . . . . . . Minaprine 200mg 39 25 37 13 Flexible Oral 100mg to 400mg NI 186mg
. . . . . . . Minaprine 300mg 43 22 40 12 Flexible Oral 100mg to 400mg NI 279mg
. . . . . . . Minaprine 400mg 37 22 37 13 Flexible Oral 100mg to 400mg NI 352mg
. . . . . . . Placebo 37 18 39 13 NI Oral NI NI NI
Amsterdam (2003) USA Somerset Pharmaceuticals, Inc.  2 Secondary/Tertiary Care Major depressive disorder, single or recurrent episode 8 weeks Selegiline 149 94 41.2 11.6 Fixed Transdermal 20mg 20mg NI
. . . . . . . Placebo 152 99 43.5 10 Fixed Transdermal NI NI NI
Bakish (1992) Canada NI 2 NI Major depressive episode 6 weeks Moclobemide 58 26 42 10.9 Flexible Oral NI to 600mg NI to 600mg 492mg
. . . . . . . Placebo 56 20 44 10.7 Flexible Oral NI NI NI
Bellak (1966) USA *MH 2 Secondary/Tertiary Care Depression 4 weeks Placebo 25 NI NI NI NI NI NI NI NI
. . . . . . . Phenelzine 25 NI NI NI NI NI NI NI NI
Benes (2011) Germany GSK 2 NI At least mild depressive symptoms 12 weeks Placebo 67 45 59.5 11.3 Flexible to week 7, then fixed Oral NI NI NI
. . . . . . . Ropinirole 198 144 58.2 11.4 Flexible to week 7, then fixed Oral 0.5 mg to 4 mg NI 1.9 mg
Bodkin (2002) NI Somerset Pharmaceuticals 2 Secondary/Tertiary Care Major depressive disorder, single or recurrent episode 6 weeks Placebo 88 53 43.2 10.8 Fixed Transdermal NI NI NI
. . . . . . . Selegiline 89 53 41.4 10.9 Fixed Transdermal 20mg 20mg 20mg
Botte (1992) NI NI 2 NI Unipolar depression, neurotic depression 6 weeks Placebo 24 16 43.33 9.9 NI NI NI NI NI
. . . . . . . Moclobemide 23 13 51.39 12.69 Flexible Oral 300mg to 600mg 200mg to 600mg NI
Casacchia (1984) Italy NI 2 Secondary/Tertiary Care Unipolar psychotic depression, neurotic depression 4 weeks Moclobemide 18 8 49.5 12.8 Flexible Oral NI 150mg to 450mg 297.2mg
. . . . . . . Placebo 16 11 49 11.4 Flexible Oral NI 150mg to 400mg 212.5mg
Chouinard (1993) Canada, UK NI 2 Secondary/Tertiary Care Major depressive episode 6 weeks Placebo 109 66 40.200000000000003 18-64 (range) Fixed Oral NI NI NI
. . . . . . . Brofaromine 111 57 41.2 18-64 (range) Fixed Oral 75mg to 150mg NI NI
Coleman (1999) USA Glaxo Wellcome Inc.  2 NI Moderate to severe depression 8 weeks Placebo 124 73 38.5 18-65 (range) Flexible Oral NI NI NI
. . . . . . . Bupropion SR 122 68 38.1 18-64 (range) Flexible Oral 150mg to 400mg 100mg to 365mg 290mg
Coleman (1999) USA Glaxo Wellcome Inc.  2 NI Moderate to severe depression 8 weeks Placebo 152 92 36.700000000000003 19-62 (range) Flexible Oral NI NI NI
. . . . . . . Bupropion 150 95 36.6 18-67 (range) Flexible Oral 150mg to 400mg NI NI
Corrigan (2000) USA NI 4 NI Major depression, single episode or recurrent episode 8 weeks Placebo 35 NI NI NI Fixed Oral NI NI NI
. . . . . . . Pramipexole 0.375mg 36 NI NI NI Fixed Oral 0.375mg 0.375mg 0.375mg
. . . . . . . Pramipexole 1mg 35 NI NI NI Fixed Oral 1mg 1mg 1mg
. . . . . . . Pramipexole 5mg 33 NI NI NI Fixed Oral 5mg 5mg 5mg
Croft (1999) NI Glaxo Wellcome Inc.  2 NI Moderate to severe depression 8 weeks Placebo 121 61 37.4 19-64 (range) Flexible Oral NI NI NI
. . . . . . . Bupropion SR 120 61 35.9 19-70 (range) Flexible Oral 150mg to 400mg 127mg to 361mg 293mg
Davidson (1988) NI Hoffmann La Roche 2 NI Major or minor depression 6 weeks Isocarboxazid 68 37 41.9 NI Flexible Oral NI NI 49.3mg
. . . . . . . Placebo 62 35 41.9 NI Flexible Oral NI NI NI
DelBello (2014) USA Somerset Pharmaceutical, Inc.  2 Secondary/Tertiary Care Moderate or severe Major Depressive Disorder 8 weeks Placebo 156 104 14.7 1.6 Flexible Transdermal NI NI NI
. . . . . . 12 weeks Selegiline 152 93 14.8 1.62 Flexible Transdermal 6mg to 12mg NI NI
Feiger (2006) USA Somerset Pharmaceutical, Inc.  2 NI Moderate or severe Major Depressive Disorder 8 weeks Selegiline 132 81 42 NI Flexible Transdermal 6mg to 12mg 6mg to 12mg NI
. . . . . . . Placebo 133 71 42 NI Flexible Transdermal NI NI NI
Feighner (1984) NI NI 2 Secondary/Tertiary Care Major depressive disorder 4 weeks Placebo 22 19 49 22-78 (range) NI Oral NI NI NI
. . . . . . . Bupropion 44 30 43.9 20-70 (range) Flexible Oral NI to 600mg 300mg to 600mg 392mg
Georgotas (1986) USA NIMH 2 NI Major depressive disorder 7 weeks Placebo 28 15 64.7 7.6 Flexible Oral NI NI NI
. . . . . . . Phenelzine 22 13 65.5 4.4000000000000004 Flexible Oral NI NI 53.90mg
Giller (1982) USA NIMH, Hoffman-LaRoche 2 Secondary/Tertiary Care Depression 6 weeks Placebo NI NI NI NI Flexible Oral NI NI 73mg
. . . . . . . Isocarboxazid NI NI NI NI Flexible Oral NI NI 48mg
GlaxoSmithKline (1980) USA GSK 3 Community Major depressive disorder 6 weeks Bupropion 150-450mg 52 35 36.4 21-67 (range) Flexible Oral 150mg to 450mg NI NI
. . . . . . . Bupropion 300-900mg 23 13 37.799999999999898 21-62 (range) Flexible NI 300mg to 900mg NI NI
. . . . . . . Placebo 47 31 37.4 21-60 (range) Flexible Oral NI NI NI
GlaxoSmithKline (1985) USA, Canada GSK 3 Secondary/Tertiary Care Depressive disorder 4 weeks Placebo 43 20 51.9 25-78 (range) Fixed Oral NI NI NI
. . . . . . . Bupropion 300mg 45 18 52.4 26-80 (range) Fixed Oral 300mg 300mg NI
. . . . . . . Bupropion 450mg 40 18 47.5 20-73 (range) Fixed Oral 450mg 450mg NI
GlaxoSmithKline (1993) USA GSK 5 NI NI 8 weeks Placebo 124 80 40.700000000000003 11.6 NI NI NI NI NI
. . . . . . . Bupropion SR 100mg 119 77 39.6 11.9 Fixed NI 100mg NI NI
. . . . . . . Bupropion SR 200mg 120 65 39.6 10.4 Fixed NI 200mg NI NI
. . . . . . . Bupropion SR 300mg 120 70 39.9 11.4 Fixed NI 300mg NI NI
. . . . . . . Bupropion SR 400mg 119 66 38.799999999999898 11.7 Fixed NI 400mg NI NI
GlaxoSmithKline (1994) USA GSK 3 Secondary/Tertiary Care Major depressive disorder 8 weeks Bupropion 50-150 152 90 39.1 12.2 Flexible Oral 50mg to 150mg 50mg to 150mg NI
. . . . . . . Placebo 154 99 38.200000000000003 11.4 NI Oral NI NI NI
. . . . . . . Bupropion 100-300 150 98 37.200000000000003 11.3 Flexible Oral 100mg to 300mg 100mg to 300mg NI
Han (2012) South Korea Korea Research Foundation Grant 2 Community MDD and problematic online game play 8 weeks Placebo 28 0 18.100000000000001 6.2 NI NI NI NI NI
. . . . . . . Bupropion 29 0 21.2 8 Fixed Oral 150mg to 300mg NI NI
Iosifescu (2022) USA Xsome Therapeutics 2 NI Major depressive disorder 6 weeks Dextromethorphan- Bupropion 156 95 42.1 12.8 NI Oral 45mg to 105mg NI NI
. . . . . . . Placebo 162 117 41.2 13.77 NI Oral NI NI NI
Jarrett (1999) NI NI 2 Community Major depressive disorder, atypical features 8.8 weeks Phenelzine 36 25 38.700000000000003 9.7799999999999905 NI NI 0.85mg/kg to 1mg/kg NI 64mg
. . . . . . 10 weeks Placebo 36 22 40.299999999999898 10.08 NI NI NI NI NI
Kusalic (1993) NI NI 2 NI Major depressive episode 6 weeks Placebo 9 NI NI NI Flexible Oral NI NI NI
. . . . . . . Moclobemide 11 NI NI NI Flexible Oral NI NI 482.60mg
Larsen (1989) Denmark NI 2 Secondary/Tertiary Care Major depressive episode 6 weeks Placebo 18 12 57 25-76 (range) Flexible Oral NI NI NI
. . . . . . . Moclobemide 22 15 51 28-70 (range) Flexible Oral NI to 300mg NI to 300mg NI
Learned (2012a) Australia, Belgium, Bulgaria, Canada, Esto*a, Finland, France, Germany, India, Poland, Slovakia, and South Africa GSK 2 NI Major depressive disorder 10 weeks Placebo 126 46 41.9 11.79 Fixed Oral NI NI NI
. . . . . . . GSK372475 134 51 43 12.07 Fixed Oral 1.5mg to 2mg 1mg to 2mg NI
Learned (2012b) Bulgaria, Canada, Chile, Costa Rica, Croatia, France, Germany, India, Italy, and Poland GSK 2 NI Major depressive disorder 10 weeks Placebo 156 39 41.8 10.89 Fixed Oral NI NI NI
. . . . . . . GSK372475 171 54 42.4 11.64 Fixed Oral 1mg to 1.5mg 1mg to 1.5mg NI
Liebowitz (1984) NI Public Health Service 2 Community Atypical depression 6 weeks Placebo 24 14 37.700000000000003 8.9 Flexible Oral NI NI NI
. . . . . . . Phenelzine 15 7 33.799999999999898 9.3000000000000007 Flexible Oral 15mg to 90mg 60mg to 90mg 74mg
Mann (1989) USA Irma Hirschl and Mallinckrodt Foundations 2 Secondary/Tertiary Care Major depressive episode 6 weeks Placebo 22 17 40.200000000000003 10.7 Flexible NI NI NI NI
. . . . . . . Selegiline 22 16 45.2 12.3 Flexible Oral NI NI to 50mg NI
Nair (1995) Canada, Denmark, UK NI 2 Secondary/Tertiary Care Major depressive episode 7 weeks Moclobemide 36 25 67 (median) 60-90 (range) Fixed Oral 400mg 400mg NI
. . . . . . . Placebo 35 25 71 (median) 62-89 (range) Fixed Oral NI NI NI
Ose (1992) NI NI 2 NI Major depressive episode 4 weeks Moclobemide 35 21 49 (median) 24-79 (range) Fixed Oral 300mg to 500mg 300mg to 500mg NI
. . . . . . . Placebo 33 18 50 (median) 30-72 (range) Fixed Oral NI NI NI
Parnetti (1993) Italy Gruppo Sanofi 2 Secondary/Tertiary Care Prolonged depressive reaction 12 weeks Minapramine 63 36 71.599999999999895 6.5 Fixed Oral 200mg 200mg 200mg
. . . . . . . Placebo 67 47 71.3 6.6 Fixed Oral NI NI NI
Quitkin (1990) USA *MH; NHCRC 2 NI Major, minor, or intermittent depression 6 weeks Phenelzine 33 NI 38.9 NI Fixed Oral 90mg 45mg to 90mg NI
. . . . . . . Placebo 34 NI 30.1 NI Fixed Oral NI NI NI
Raft (1981) USA *H 2 Secondary/Tertiary Care Depression 5 weeks Phenelzine NI NI NI NI Fixed Oral 90mg 30mg to 90mg 90mg
. . . . . . . Placebo NI NI NI NI Fixed Oral NI NI NI
Rampello (1991) Italy NI 2 Secondary/Tertiary Care Primary major u*polar depression or bipolar affective disorder depressed 6 weeks Minaprine 10 NI NI NI Fixed Oral 100mg 100mg to 200mg NI
. . . . . . . Placebo 10 NI NI NI Fixed Oral NI NI NI
Raskin (1972) USA *MH 2 Secondary/Tertiary Care Depression 5 weeks Placebo 111 NI NI NI Fixed Oral NI NI NI
. . . . . . . Phenelzine 110 72 37 (median) NI Fixed Oral 45mg 22.5mg to 45mg NI
Ravaris (1976) NI Public Health Service; Warner Lambert Research Institute 3 Primary care Depression 6 weeks Phenelzine 60mg 21 NI 43.1 15.12 NI Oral 60mg 60mg NI
. . . . . . . Phenelzine 30mg 21 NI 41.2 16.5 Fixed Oral 30mg 30mg NI
. . . . . . . Placebo 21 NI 38.9 10.1 Fixed Oral NI NI NI
Reimherr (1998) USA Glaxo Wellcome Inc.  3 NI Major depression 8 weeks Placebo 121 69 40.200000000000003 12.2 Fixed Oral NI NI NI
. . . . . . . Bupropion SR 150mg 121 86 38.299999999999997 11 Fixed Oral 150mg 150mg NI
. . . . . . . Bupropion SR 300mg 120 92 38.6 10.7 Fixed Oral 300mg 300mg NI
Rickels (1970) USA Public Health Service 2 Community, Primary care, Secondary/Tertiary Care Moderate depression 4 weeks Methylphenidate NI NI NI NI Fixed Oral 15mg 15mg NI
. . . . . . . Placebo NI NI NI NI Fixed Oral NI NI NI
Riesenberg (2010) USA Rexahn Pharmaceuticals 4 NI Major depression 8 weeks Placebo 21 11 42.5 10.8 Fixed Oral NI NI NI
. . . . . . . RX-10100 5mg 21 11 44.8 11.9 Fixed Oral 5mg 5mg NI
. . . . . . . RX-10100 10mg 16 7 42.6 11.97 Fixed Oral 10mg 10mg NI
. . . . . . . RX-10100 15mg 17 9 39.4 11.27 Fixed Oral 15mg 15mg NI
Robin (1958) UK NI 2 Secondary/Tertiary Care Depression 4 weeks Placebo 23 13 39.5 13.9 Flexible Oral NI NI NI
. . . . . . . Methylphenidate 22 16 37.5 11.5 Flexible Oral 20mg to 40mg NI NI
Rowan (1980) NI NI 2 Secondary/Tertiary Care Depression or mixed anxiety/depression 6 weeks Phenelzine NI NI NI NI Flexible Oral 45mg to 75mg NI NI
. . . . . . . Placebo NI NI NI NI Fixed Oral NI NI NI
Tomarken (2004) USA Glaxo Wellcome Inc.  2 Community Major depression 6 weeks Bupropion SR 10 6 39.4 9.8 Fixed Oral 300mg to 400mg 100mg to 400mg NI
. . . . . . . Placebo 9 6 37.5 7.8 Fixed Oral NI NI NI
Ucha (1990) NI NI 2 NI Major depression 6 weeks Placebo 24 13 42.2 15.1 Flexible Oral NI NI 5.6 tabs per day
. . . . . . . Moclobemide 24 16 40.5 15.6 Flexible Oral 300mg to 600mg NI 405mg
Versiani (1989) NI NI 2 NI Major depression 6 weeks Moclobemide 164 124 44 12 Flexible Oral 300mg to 600mg NI NI
. . . . . . . Placebo 162 123 42 12 Flexible Oral NI NI NI
Versiani (1990) Brazil NI 2 NI Major depression 6 weeks Moclobemide 25 NI NI NI NI Oral 600mg 600mg 600mg
. . . . . . . Placebo 25 NI NI NI NI Oral NI NI NI
Versiani (1997) NI NI 2 Secondary/Tertiary Care Dysthymia 6 weeks Moclobemide 108 73 41 12 Flexible Oral 75mg to 750mg 75mg to 750mg 633mg
. . . . . . . Placebo 104 71 40 11 Flexible Oral NI NI NI
White (1984) USA NI 2 Secondary/Tertiary Care Major depression 4 weeks Tranylcypromine 63 14 38 NI Flexible Oral 30mg to 60mg NI 44.4mg
. . . . . . . Placebo 59 21 39 NI Flexible Oral NI NI NI
Zarate (2006) NI NI 2 Secondary/Tertiary Care Major depression 8 weeks Memantine 16 9 47.1 12.3 Flexible Oral 5mg to 20mg 5mg to 20mg 19.4mg
. . . . . . . Placebo 16 7 46.1 9.4 Flexible Oral NI NI NI
Zisook (1985) NI NI 2 Secondary/Tertiary Care Major or minor depression 6 weeks Isocarboxazid NI NI NI NI Flexible Oral NI to 80mg NI 39.00mg
. . . . . . . Placebo NI NI NI NI NI NI NI NI NI

Table 2. characteristics of included studies that did not report anhedonia scores. NI=no information reported

Primary outcome: reduction in anhedonia scores at 8 weeks (from 4 to 12 weeks)

Figure X Forest plot for symptoms of anhedonia (primary outcome) comparing pro-dopaminergic interventions vs placebo for individuals with anhedonia at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95%CI: 95% confidence intervals, SD: standard deviation.

6 studies contributed with data to the meta-analysis with a total of 2076 participants (1140 allocated to pro-dopaminergic interventions, 936 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with a SMD of -0.244 (95%CI from -0.456 to -0.031). The study results presented an I2 value of 67.7% (95%CI from 23.4% to 86.4%) and a tau2 value of 0.025 (accounting for a 95% prediction interval from -0.74 to 0.252).

Risk of bias

Evidence for the efficacy of pro-dopaminergic interventions vs placebo in improving anhedonia was rated moderate for risk of bias. 50% of the included studies had an overall high risk of bias while the other 50% had moderate risk of bias, primarily due to missing outcome data, issues with outcome measurement, and selective reporting of findings. The extent to which the result was affected by across-study biases is unclear and all included studies were rated at least moderate in domain 5, selection of results. This result was judged to be at moderate risk of bias due to indirectness as while there was no clear indication of indirectness in terms of population, comparator, or outcomes, 80% of the studies measured the same intervention, bupropion.

Sensitivity analyses

We performed a series of random effects network meta-analyses on the MADRS “inability to feel” item (aggregated IPD from 34 studies, 14054 participants). First, we included all the available studies and compared all the antidepressants against placebo.

The comparative effect of buproprion versus placebo was -0.12 (SMD, 95%CI from -0.25 to 0.00; 34 studies, 14054 participants), lower than what we could observe from the retrieved data (random effects pairwise meta-analysis, bupropion versus placebo): -0.22 (SMD, 95%CI from -0.44 to 0.01; 5 studies, 2020 participants).

We also performed a random effects pairwise meta-analysis of buproprion versus placebo based on the aggregated IPD, resulting in estimates comparable to the network meta-analytical model (SMD -0.12, 95%CI from -0.29 to 0.05; 4 studies, 1085 participants).

Finally, we performed a random effects pairwise meta-analysis including aggregate data from both sources (IPD and retrieved as aggregated). As three studies (Hewett 2009 - 87997883, Hewett 2010a - 87997755, Koshino 2013 - 87997374) were available in both sources, we prioritised aggregate IPD over data retrieved as aggregated. The comparative effect of bupropion versus placebo was -0.19 (SMD, 95%CI from -0.33 to 0.04; 6 studies, 2489 participants)

Sub-group and meta-regression analyses

We did not find sufficient data (i.e. at least ten studies) to conduct a meta-regression for the investigated predictors. Insufficient data existed for age, proportion of females, anhedonia baseline score, anxiety baseline score, reward baseline score, and treatment duration.

Secondary outcome: Reduction in mean anxiety score at 8 weeks (from 4 to 12 weeks)

Figure X Forest plot for symptoms of anxiety (secondary outcome) comparing pro-dopaminergic interventions vs placebo for individuals with anxiety at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95%CI: 95% confidence intervals, SD: standard deviation.

11 studies contributed with data to the meta-analysis with a total of 3517 participants (2077 allocated to pro-dopaminergic interventions, 1440 allocated to pill placebo.

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with a SMD of -0.166 (95%CI from -0.243 to -0.088). The study results presented an I2 value of 0% (95%CI from 0% to 60.2%) and a tau2 value of 0 (accounting for a 95% prediction interval from -0.251 to -0.08).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age, proportion of females, and anxiety baseline score. Insufficient data existed for anhedonia baseline score, reward baseline score, and treatment duration.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was not significant.
  • The meta-regression for anxiety baseline score was not significant.

Risk of Bias

Secondary outcome: Dropouts due to any reason

Figure X Forest plot for dropouts due to any reason for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

50 studies contributed with data to the meta-analysis with a total of 9168 participants (5234 allocated to pro-dopaminergic interventions, 3934 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 0.959 (95%CI from 0.782 to 1.177). The study results presented an I2 value of 61.7% (95%CI from 48.1% to 71.8%) and a tau2 value of 0.24 (accounting for a 95% prediction interval from -1.045 to 0.962).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age, proportion of females, and anxiety baseline score. Insufficient data existed for anhedonia baseline score, reward baseline score, and treatment duration.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was not significant.
  • The meta-regression for anxiety baseline score was not significant.

Risk of bias

Secondary outcome: dropouts due to side effects

Figure X Forest plot for dropouts due to adverse events for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

41 studies contributed with data to the meta-analysis with a total of 8473 participants (4831 allocated to pro-dopaminergic interventions, 3642 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.876 (95%CI from 1.407 to 2.501). The study results presented an I2 value of 34.8% (95%CI from 4.4% to 55.6%) and a tau2 value of 0.229 (accounting for a 95% prediction interval from -1.045 to 1.636).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age, proportion of females, and anxiety baseline score. Insufficient data existed for anhedonia baseline score, reward baseline score, and treatment duration.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was significant (beta = -2.768, 95% CI from -4.914 to -0.621).
  • The meta-regression for anxiety baseline score was not significant.

Risk of bias

Secondary outcome: nausea

Figure X Forest plot for nausea for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

24 studies contributed with data to the meta-analysis with a total of 6489 participants (3620 allocated to pro-dopaminergic interventions, 2869 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.456 (95%CI from 1.182 to 0.584). The study results presented an I2 value of 27.2% (95%CI from 0% to 55.9%) and a tau2 value of 0.064 (accounting for a 95% prediction interval from -0.189 to 0.94).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age and proportion of females. Insufficient data existed for anhedonia baseline score, anxiety baseline score, reward baseline score, and treatment duration.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was not significant.

Risk of bias

Secondary outcome: headache

Figure X Forest plot for headaches for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

26 studies contributed with data to the meta-analysis with a total of 6527 participants (3663 allocated to pro-dopaminergic interventions, 2864 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.16 (95%CI from 1.03 to 1.307). The study results presented an I2 value of 0% (95%CI from 0% to 43.2%) and a tau2 value of 0 (accounting for a 95% prediction interval from 0.007 to 0.29).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age and proportion of females. Insufficient data existed for anhedonia baseline score, anxiety baseline score, reward baseline score, and treatment duration.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was not significant.

Risk of bias

Secondary outcome: insomnia

Figure X Forest plot for insomnia for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

22 studies contributed with data to the meta-analysis with a total of 5875 participants (3253 allocated to pro-dopaminergic interventions, 2622 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.791 (95%CI from 1.424 to 2.251). The study results presented an I2 value of 5.3% (95%CI from 0% to 37.5%) and a tau2 value of 0.03 (accounting for a 95% prediction interval from 0.15 to 1.015).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age and proportion of females. Insufficient data existed for anhedonia baseline score, anxiety baseline score, reward baseline score, and treatment duration.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was not significant.

Risk of bias

Secondary outcome: constipation

Figure X Forest plot for dropouts due to adverse events for the comparison of pro-dopaminergic interventions vs placebo at 8 (4-12) weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

19 studies contributed with data to the meta-analysis with a total of 4818 participants (2708 allocated to pro-dopaminergic interventions, 2110 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.551 (95%CI from 1.248 to 1.927). The study results presented an I2 value of 0% (95%CI from 0% to 48.9%) and a tau2 value of 0 (accounting for a 95% prediction interval from 0.182 to 0.695).

There were no significant subgroup differences between participants assigned to different classes of drug.

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age, proportion of females, and treatment duration. Insufficient data existed for anhedonia baseline score, anxiety baseline score, and reward baseline score.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was not significant.
  • The meta-regression for treatment duration was not significant.

Risk of bias

Secondary outcome: dizziness

Figure X Forest plot for dizziness for the comparison of pro-dopaminergic interventions vs placebo at 8 (4-12) weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

22 studies contributed with data to the meta-analysis with a total of 5469 participants (2996 allocated to pro-dopaminergic interventions, 2473 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 1.716 (95%CI from 1.322 to 2.227). The study results presented an I2 value of 25.8% (95%CI from 0% to 56%) and a tau2 value of 0.08 (accounting for a 95% prediction interval from -0.103 to 1.183).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age and proportion of females. Insufficient data existed for anhedonia baseline score, anxiety baseline score, reward baseline score, and treatment duration.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was not significant.

Risk of bias

Secondary outcome: dry mouth

Figure X Forest plot for dry mouth for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

24 studies contributed with data to the meta-analysis with a total of 6308 participants (3431 allocated to pro-dopaminergic interventions, 2877 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed an effect favouring pro-dopaminergic interventions with an OR of 2.117 (95%CI from 1.679 to 2.67). The study results presented an I2 value of 36.1% (95%CI from 0% to 61%) and a tau2 value of 0.08 (accounting for a 95% prediction interval from 0.126 to 1.374).

Sub-group and meta-regression analyses

We found enough data (i.e. at least ten studies) to conduct a meta-regression for age, proportion of females, and treatment duration. Insufficient data existed for anhedonia baseline score, anxiety baseline score, and reward baseline score.

  • The meta-regression for age was not significant.
  • The meta-regression for proportion of females was significant (beta = -2.075, 95% CI from -3.836 to -0.314).
  • The meta-regression for treatment duration was not significant.

Risk of bias

Secondary outcome: vomiting

Figure X Forest plot for vomiting for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95%CI: 95% confidence intervals.

5 studies contributed with data to the meta-analysis with a total of 962 participants (614 allocated to pro-dopaminergic interventions, 348 allocated to pill placebo).

The comparative effect of pro-dopaminergic interventions versus placebo showed a comparable effect not excluding the null effect with an OR of 1.898 (95%CI from 0.901 to 1.386). The study results presented an I2 value of 2.2% (95%CI from 0% to 79.7%) and a tau2 value of 0 (accounting for a 95% prediction interval from -0.204 to 1.485).

Sub-group and meta-regression analyses

We did not find sufficient data (i.e. at least ten studies) to conduct a meta-regression for the investigated predictors. Insufficient data existed for age, proportion of females, anhedonia baseline score, anxiety baseline score, reward baseline score, and treatment duration.

Risk of bias

Reporting bias

Summary of evidence tables

Source of evidence    Summary of the association    Bias due to study limitations (internal validity)  Bias due to reporting bias (external validity)  Bias due to indirectness    Bias due to other reasons 
Pro-dopaminergic intervention. vs placebo in depressed patients with symptoms of anhedonia   N=6, n=2079; random effects: SMD= -0.24, 95%CI: -0.46, -0.03, I2=68%, t2=0.025  Moderate risk: 50% of the studies had an overall high risk of bias (due to missing outcome data, and issues with outcome measurement and selective reporting of findings. 50% of studies had a moderate risk of bias.)  Moderate risk: all studies were rated at least some concerns in RoB2 domain 5, selection of results. The impact of the bias on the magnitude and direction of the effects of pro-dopaminergic agonists is unclear.  Moderate risk: 80% of the studies measured the same intervention, bupropion.For outcomes. 50% of studies measured anhedonia using the MEI, 30% using the MADRS anhedonia item and 20% using the IDS-IVR-30/IDS-C-30 Pleasure Scale  No other clear indication of indirectness in terms of population, interventions, and outcomes.   No clear indication of other biases. 
Pro-dopaminergic interventions vs placebo in improving anxiety  N=11, n=3517; random effects: SMD=-0.17, 95%CI: -0.24, -0.09, I2=0%, t2 <0.001  Moderate risk: 60% of studies were rated moderate risk of bias while 10% were rated as high risk of bias. This was primarily due to domain 2- deviation from intended interventions.  Moderate risk: 60% of studies were rated moderate risk in domain 5 of RoB2. The impact of the bias on the magnitude and direction of the effects is unclear.  Moderate risk: 70% of studies contributing to the analysis tested bupropion   No clear indication of other biases. 
Acceptability of pro-dopaminergic interventions vs placebo  N=50, n=9159; Random effects: OR=0.91, 95%CI: 0.73,  1.14, I2=72% t2=0.334  Low risk: 10% of studies had an overall high risk of bias, primarily due to concerns over outcome measurement, while 32% were rated moderate risk of bias.  Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.  Low risk: studies included utilised a variety of interventions used in differing populations in a range of settings.  No clear indication of other biases. 
Constipation reported for pro-dopaminergic interventions vs placebo  N=19, n=4809; random effects: OR=1.55, 95%CI: 1.25, 1.93, I2=0% t2=<.001  Low risk: 79% of studies were rated as low risk of bias and no studies were rated high risk of bias.  Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.  Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.  No clear indication of other biases 
Dizziness reported for pro-dopaminergic interventions vs placebo  N=22, n=5460, random effects OR=1.72, 95%CI: 1.32, 2.24, I2=26% t2=0.08  Low risk: 59% of studies were rated low risk of bias and only 5% were rated high risk of bias.  Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.  Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.  No clear indication of other biases 
Dry mouth reported for pro-dopaminergic interventions vs placebo  N=24, n=6299, random effects OR=2.12, 95%CI: 1.68, 2.67, I2=36% t2=0.08  Low risk: 75% of studies were rated low risk of bias for RoB2 while only 4% were rated high risk of bias.  Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.  Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.  No clear indication of other biases 
Headache reported for pro-dopaminergic interventions vs placebo  N=26, n=6518, random effects, OR=1.16, 95%CI: 1.03, 1.31, I2=0% t2=<0.001  Low risk: 62% of studies were rated low risk for RoB2 while 27% were rated as moderate risk with scores of ‘some concerns’ spread out across domains in no clear pattern.  Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.  Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.  No clear indication of other biases 
Nausea reported for pro-dopaminergic interventions vs placebo  N=24, n=6480, random effects OR=1.46, 95%CI: 1.18, 1.78, I2=27% t2=0.06  Low risk: 71% of studies were rated low risk for RoB2 while 21% were rated moderate.  Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.   Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.  No clear indication of other biases 
Insomnia reported for pro-dopaminergic interventions vs placebo  N=22, n=5866, random effects OR=1.80, 95%CI: 1.43, 2.25, I2=5% t2=0.03  Low risk: 68% of studies were rated as low risk for RoB2 while 28% were rated as moderate risk.  Low risk: the impact of bias on the magnitude and direction of the effects of pro-dopaminergic agonists is low.  Low risk: studies included in the analysis utilised a variety of interventions used in differing populations in a range of settings.  No clear indication of other biases. 
Vomiting reported for pro-dopaminergic interventions vs placebo  N=5, n=962, random effects OR=1.89, 95%CI: 0.90, 4.00, I2=2% t2<0.001  Moderate risk: 80% of studies were rated as moderate risk and 20% as high risk due to concerns in RoB2 domains 3 (missing outcome data) and 4 (measuring the outcome)   Moderate risk: the impact of the bias on the magnitude and direction of the effects of pro-dopaminergic interventions is unclear.  Moderate risk: only 5 studies contributed to the analysis with a relatively small number of participants. A variety of interventions were tested.   No clear indication of other biases. 

Abbreviations

  • CI: Confidence Interval

  • GALENOS: Global Alliance for Living Evidence on aNxiety depressiOn and pSychosis

  • IPD: Individual Participant Data

  • OR: Odds Ratio

  • N: number of studies

  • n: number of participants

  • NI: No Information

  • SD: Standard Deviation

  • SMD: Standard Mean Difference

  • REML: Restricted Maximum Likelihood

  • RoB2: Risk of Bias 2

  • ROB-ME: Risk of Bias for Missing Evidence

Software Used

We used R version 4.3.1 (R Core Team 2023) and the following packages; meta (Balduzzi, Rucker, and Schwarzer, 2019); dplyr (Wickham et al, 2023); readxl (Wickham and Bryan, 2023); kableExtra (Zhu, 2024).

References

  • Higgins, J. P., Savović, J., Page, M. J., Elbers, R. G., & Sterne, J. A. (2019). Assessing risk of bias in a randomized trial.  Cochrane handbook for systematic reviews of interventions, 205-228.

  • Flemyng, E., Moore, T. H., Boutron, I., Higgins, J. P., Hróbjartsson, A., Nejstgaard, C. H., & Dwan, K. (2023). Using Risk of Bias 2 to assess results from randomised controlled trials: guidance from Cochrane. BMJ Evidence-Based Medicine, 28(4), 260-266.

  • Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., ... & Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.  Bmj, 372.

  • Page, M. J., Sterne, J. A., Boutron, I., Hróbjartsson, A., Kirkham, J. J., Li, T., ... & Higgins, J. P. (2023). ROB-ME: a tool for assessing risk of bias due to missing evidence in systematic reviews with meta-analysis.  bmj, 383